Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus–Merzbacher disease

Nafisinia, Michael; Sobreira, Nara; Riley, Lisa G.; Gold, Wendy; Uhlenberg, Birgit; Weiß, Claudia; Boehm, Corinne D.; Prelog, Kristina; Ouvrier, Robert; Christodoulou, John

doi:10.1038/ejhg.2017.119

Cited by 28 publications

(29 citation statements)

References 43 publications

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“…Both heterozygous and homozygous disease-causing variants in several ARS genes have been reported 11 . Biallelic damaging variants in ARS2 genes, encoding mitochondriallocalized enzymes, tend to cause mitochondrial encephalopathies, whereas biallelic damaging variants in ARS1 genes, encoding cytoplasm-localized enzymes, tend to cause epileptic encephalopathies or other systemic conditions 3,4,[12][13][14][15] . Interestingly, certain variants in ARS genes show peripheral neuropathy (i.e., Charcot-Marie-Tooth syndrome) with dominant inheritance, at least partially explained by toxic gain-of-function effects of mutant proteins binding to neuropilin-2 [16][17][18][19][20][21][22] .…”

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confidence: 99%

Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

Wang

Sievert

et al. 2020

Nat Commun

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Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Here, we identify biallelic missense and frameshift mutations in NARS1 in seven patients from three unrelated families with microcephaly and neurodevelopmental delay. Patient cells show reduced NARS1 protein, impaired NARS1 activity and impaired global protein synthesis. Cortical brain organoid modeling shows reduced proliferation of radial glial cells (RGCs), leading to smaller organoids characteristic of microcephaly. Single-cell analysis reveals altered constituents of both astrocytic and RGC lineages, suggesting a requirement for NARS1 in RGC proliferation. Our findings demonstrate that NARS1 is required to meet protein synthetic needs and to support RGC proliferation in human brain development.

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confidence: 99%

Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

Wang

Sievert

et al. 2020

Nat Commun

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“…8,9 Bi-allelic variants in RARS have been shown to cause hypomyelinating leukodystrophy in seven patients. 3,4 In this study, we added two cases from two unrelated families from two different geographic areas, sharing the same novel variant, c.2T > C, which leads to the loss of the initiating methionine.…”

Section: Discussionmentioning

confidence: 99%

“…2 Newly emerged molecular technolo-gies, such as next generation sequencing (NGS), allowed identification ofnovel leukodystrophies even extremely rare ones observed in only few individuals. 3,4 Defects in genes encoding cytoplasmic and/or mitochondrial aminoacyl tRNA (transfer ribonucleic acid) synthetase (aaRS) enzymes were found to be associated with the pathogenesis of some leukodystrophies. aaRS enzymes catalyze the binding of tRNAs to their cognate amino acids (AAs) leading to protein synthesis in mitochondria and ribosome.…”

Section: Introductionmentioning

confidence: 99%

“…Studies reported that variants in RARS gene, encoding cytoplasmic arginyl-tRNA synthetase, causehypomyelinating leukodystrophy. 3,4 Herein, we presented two additional children with hypomyelinating leukodystrophy caused by a homozygous variant in RARS. We also showed that spinal cord involvement may occur due to RARS-related hypomyelination.…”

Section: Introductionmentioning

confidence: 99%

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Hypomyelinating Leukodystrophy with Spinal Cord Involvement Caused by a Novel Variant in RARS: Report of Two Unrelated Patients

et al. 2019

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Leukodystrophies are heterogeneous group of genetic white matter disorders with a wide range of neurologic and systemic manifestations. Defects in genes encoding aminoacyl tRNA (transfer ribonucleic acid) synthetase enzymes (aaRSs) are recently identified as the etiology of some leukodystrophies. Herein, we described two unrelated children referred to Children's Medical Center, Tehran, Iran, with developmental delay, nystagmus, seizures, psuedo-bulbar palsy and dystonia. Whole exome sequencing (WES) in both patients identified a homozygous (c.2T > C) variant in exon one of RARS gene, encoding cytoplasmic arginyl-tRNA synthetase. Our finding was confirmed by segregation analysis. In silico analyses of the c.2T > C variant showed its possible pathogenic role due to the absence of the start codon. Severe hypomyelination was the common neuroimaging finding of both cases. Spinal cord involvement was found in one of our patients which was not previously reported in studies. We, therefore, showed that RARS-related hypomyelination might affect spinal cord.

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“…Bi-allelic mutations in genes for lysyl, glycyl, methionyl-, isoleucyl-, glutamyl-, and arginyl-tRNA synthetases have been reported. 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 Phenotypes associated with these mutations are variable and whether they arise from defects in protein synthesis has either not been explored or is controversial. However, mice haploinsufficient for GARS have a 50% decrease in enzymatic activity in vitro and in tissues, but nonetheless have a normal phenotype and lifespan.…”

Section: Introductionmentioning

confidence: 99%

Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function

Beck

et al. 2018

The American Journal of Human Genetics

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The tRNA synthetases catalyze the first step of protein synthesis and have increasingly been studied for their nuclear and extra-cellular ex-translational activities. Human genetic conditions such as Charcot-Marie-Tooth have been attributed to dominant gain-of-function mutations in some tRNA synthetases. Unlike dominantly inherited gain-of-function mutations, recessive loss-of-function mutations can potentially elucidate ex-translational activities. We present here five individuals from four families with a multi-system disease associated with bi-allelic mutations in FARSB that encodes the beta chain of the alpha2beta2 phenylalanine-tRNA synthetase (FARS). Collectively, the mutant alleles encompass a 5′-splice junction non-coding variant (SJV) and six missense variants, one of which is shared by unrelated individuals. The clinical condition is characterized by interstitial lung disease, cerebral aneurysms and brain calcifications, and cirrhosis. For the SJV, we confirmed exon skipping leading to a frameshift associated with noncatalytic activity. While the bi-allelic combination of the SJV with a p.Arg305Gln missense mutation in two individuals led to severe disease, cells from neither the asymptomatic heterozygous carriers nor the compound heterozygous affected individual had any defect in protein synthesis. These results support a disease mechanism independent of tRNA synthetase activities in protein translation and suggest that this FARS activity is essential for normal function in multiple organs.

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Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus–Merzbacher disease

Cited by 28 publications

References 43 publications

Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

Hypomyelinating Leukodystrophy with Spinal Cord Involvement Caused by a Novel Variant in RARS: Report of Two Unrelated Patients

Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function

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